The objective of this Conte Center is to study the role of the brain's reward circuits in the regulation of mood and motivation as they relate to depression and antidepressant action. The program of research contains three major strengths. First, is the multidisciplinary nature of our ongoing and proposed research. Each research area represents an integration of molecular, cellular, pharmacological, and behavioral levels of analysis aimed at obtaining a more complete understanding of the neurobiology of mood. Second, is the integration of our basic science research with the investigation of clinical populations. Third, is the extraordinary degree of integration of the various Projects to examine highly related aspects of the central hypothesis of the Center. While research in depression has focused largely on hippocampus and cerebral cortex, other neural circuits possibly involved have received much less attention. This Center focuses on one of these other circuits, namely, reward regions of brain, in particular, the VTA (ventral tegmental area) and NAc (nucleus accumbens), known to be important for motivation, reward, appetite, sleep, psychomotor activity, and circadian rhythms. A focus on the VTA-NAc makes sense given the degree to which abnormalities in these various behavioral domains are seen in patients with depression and other mood disorders. Indeed, Center research over the past 4 years has played an important role in the field by providing substantial evidence for the importance of these brain areas in animal models of depression. The Center is organized into a small Administrative Core, three scientific Cores, and five Projects. The Transgenic Core provides highly innovative tools of inducible mouse mutagenesis and viral gene transfer to Center investigators;the Behavioral Core provides an extremely broad battery of behavioral tests in mice and rats relevant to mood and motivation;and the Chromatin and Gene Regulation Core offers state-of-the-art tools to study regulation of gene expression, including changes in chromatin structure, in depression models. Project 1 focuses on the transcription factor CREB as a key regulator of the VTA-NAc and its role in mood and motivation. Subsequent Projects evaluate a series of other molecular targets in this reward circuit, which are both important regulators of CREB function and important effectors in mediating CREB's behavioral phenotype. Project 2 focuses on BDNF;Project 3 focuses on three hypothalamic peptides, MCH, orexin (hypocretin), and leptin;Project 4 focuses on Clock, NPAS2, and other circadian genes;and Project 5 focuses on studies of these same molecular targets in the VTA-NAc of depressed humans at autopsy. Work of this Center has already revealed fundamentally new insight into the molecular and cellular mechanisms that contribute to the regulation of mood and motivation under normal conditions and abnormalities in these complex behaviors seen in depression. We are now requesting funding for a second 5 year period to continue this promising avenue of multidisciplinary, innovative/and translational research.